title: Synergistic effects of 5-aminolevulinic acid based photodynamic therapy and celecoxib via oxidative stress in human cholangiocarcinoma cells.
abstract: 5-Aminolevulinic acid (ALA)-based photodynamic therapy (PDT) has the potential to kill cancer cells via apoptotic or necrotic signals that are dependent on the generation of intracellular reactive oxygen species (ROS). Celecoxib is an anti-inflammatory drug that induces intracellular ROS generation. We investigated whether the combined application of celecoxib and ALA-PDT improved the efficacy of PDT in human cholangiocarcinoma cells and in tumor bearing mice. In vitro, combined treatment of celecoxib and ALA-PDT increased phototoxicity and intracellular ROS levels after irradiation with 0.75 J/cm(2) when compared to ALA-PDT alone. Even though ROS levels increased with 0.25 J/cm(2) of irradiation, it did not influence phototoxicity. When heme oxygenase-1, a defensive protein induced by oxidative stress, was inhibited in the combined treatment group, phototoxicity was increased at both 0.25 J/cm(2) and 0.75 J/cm(2) of irradiation. We identified the combined effect of ALA-PDT and celecoxib through the increase of oxidative stress such as ROS. In vivo, about 40% tumor growth inhibition was observed with combined application of ALA-PDT and celecoxib when compared to ALA-PDT alone. The combined application of ALA-PDT and celecoxib could be an effective therapy for human cholangiocarcinoma. Moreover, use of a heme oxygenase-1 inhibitor with PDT could play an important role for management of various tumors involving oxidative stress.
authors.affiliation: National Research and Development Center for Hepatobiliary Cancer, Research Institute for Convergence of Biomedical Science and Technology, Yangsan, Republic of Korea.
authors.forename: Cy Hyun
authors.initials: CH
authors.lastname: Kim
authors.forename: Chung-Wook
authors.initials: CW
authors.lastname: Chung
authors.forename: Hye Myeong
authors.initials: HM
authors.lastname: Lee
authors.forename: Do Hyung
authors.initials: DH
authors.lastname: Kim
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Kwak
authors.forename: Young-I L
authors.initials: YI
authors.lastname: Jeong
authors.forename: Dae Hwan
authors.initials: DH
authors.lastname: Kang
mesh_terms: D000622:Aminolevulinic Acid / Q000737:chemistry / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001650:Bile Duct Neoplasms; D001653:Bile Ducts, Intrahepatic; D000068579:Celecoxib; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018281:Cholangiocarcinoma; D004357:Drug Synergism; D051547:Heme Oxygenase-1 / Q000032:analysis / Q000378:metabolism; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000187:drug effects*; D010778:Photochemotherapy / Q000379:methods*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D011720:Pyrazoles; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D000622:Aminolevulinic Acid; D051547:Heme Oxygenase-1; D000068579:Celecoxib
keywords: aminolevulinic acid; celecoxib; human cholangiocarcinoma; photodynamic therapy; reactive oxygen species